Hypoxia-Driven Rewiring: Integrative Single-Cell Multi-omics of HIF and SREBP2 Pathways in Tumor Adaptation

Dickson et al. (2023) unveiled an oxygen-sensitive, HIF-independent mechanism regulating cholesterol synthesis via SREBP2. This project aims to map, at single-cell resolution, how HIF and SREBP2 pathways are co-regulated or decoupled in hypoxic tumor microenvironments. By combining single-cell RNA-seq, ATAC-seq, and proteomics on tumor biopsies and organoids subjected to graded hypoxia, the study would reveal cell-type-specific strategies for metabolic adaptation. Are there subpopulations that preferentially activate one pathway over the other? Does rewiring between these pathways underpin therapy resistance or metastatic potential? This integrative approach could lead to the identification of novel vulnerabilities in hypoxic tumors, guiding the next generation of combinatorial therapies targeting both HIF and SREBP2.

References:

1. A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis. Anna S Dickson, Tekle Pauzaite, Esther Arnaiz, Brian Ortmann, J. West, Norbert Volkmar, Anthony W. Martinelli, Zhaoqi Li, N. Wit, Dennis Vitkup, A. Kaser, P. Lehner, J. Nathan (2023). Nature Communications.